Activity-Dependent Regulation of the Dopamine Phenotype in the Adult Substantia Nigra: Prospects for Treating Parkinson's Disease

Abstract

The motor symptoms of Parkinson’s disease (PD) are caused by degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) and the resulting depletion of DA signaling in their target structure, the dorsal striatum (the nigrostriatal pathway). PD motor symptoms are successfully alleviated by systemic administration of a blood-brain barrier permeable DA precursor (levodopa) or DA receptor agonists (Olanow et al. 2001), however these treatments are marred by side-effects in some patients (Wood 2010), and increasingly unreliable response and shortened duration of effect coupled with the emergence of dyskinesias in most patients (Stocchi et al. 2010, Stocchi & Marconi 2010). These problems probably arise from loss of physiological storage, release and reuptake of nigrostriatal DA and ensuing down-stream changes in post-synaptic signaling, and from increased DA signaling in structures outside the nigrostriatal pathway, especially when D2 agonists are used. Targeted (nigrostriatal) reconstruction of physiological DA signaling, aimed at restoring nigrostriatal DA transmission to at least the level at disease outset, ought to alleviate PD motor symptoms without side-effects. However, attempts to achieve this by replacing SNc DA cells through transplantation or endogenous repair are often hampered by poor acquisition and maintenance of the DA phenotype in the microenvironment of the adult SNc (Brundin et al. 2000, Courtois et al. 2010, Torres et al. 2005, Bauer et al. 2000).